Cardiovascular disease (atherogenesis) is the leading cause of cardiovascular mortality and morbidity in the developed world. The imaging of coronary atherosclerosis, and more specifically, methods to noninvasively assess the instability of atheromatous plaques, is critically important in the diagnosis and treatment of this disease. X-ray angiography and gray scale intravascular ultrasound (IVUS) are currently utilized in atherosclerotic plaque assessment, and both of these methods provide limited information as to the stenosis degree or plaque morphology. Unfortunately, it is now believed that neither feature is predictive of plaque vulnerability, and on the contrary, data suggests that atherosclerotic plaques that lead to infarction are often non-stenotic. New post-processing IVUS techniques include IVUS virtual histology, integrated backscatter analysis, and palpography, which can provide enhanced accuracy for detecting fibrous, fibrofatty, and necrotic core tissue. However, IVUS imaging resolution, penetration depth in calcified tissue, and tissue classification challenges are still obstacles to more comprehensive disease assessment using these post processing techniques. Thus, our current ability for assessing the instability of atherosclerotic plaques remains extremely limited. Recent research involving contrast enhanced vasa vasorum imaging and molecular imaging of plaque- associated inflammatory and angiogenic biomarkers suggests that these contrast imaging techniques can provide critical information to assess plaque instability. However, nonlinear detection strategies for microbubble contrast agents are most effective near their resonant frequency, which is typically between 1-10 MHz, much lower that the IVUS imaging frequency (20-45 MHz). Thus, IVUS catheters designed for nonlinear contrast imagings are not available. A recently demonstrated high-frequency imaging strategy utilizing the ultra- broadband response of contrast agents provides very high signal to noise, high-resolution contrast imaging at frequencies above 20 MHz, but requires a new type of dual-frequency ultra-broadband transducer. In this project, such a transducer will be designed for IVUS using micromachined piezoelectric composite (MPC) ultrasound transducer technology. A dual frequency circular array, with 8-element 5 MHz and 64-element 40 MHz components, will be developed using deep reactive ion etching and multilayering techniques. Multi- channel, multi-frequency electronics will be developed for dual mode imaging (IVUS and contrast enhanced- IVUS) utilizing the fabricated dual frequency arrays. Contrast-IVUS will be performed in in-vitro phantoms and ex-vivo tissue to assess the prototype transducer, followed by in-vivo imaging in the pre-clinical atherosclerotic standard, the familial hypercholesterimic swine. The proposed high-resolution IVUS will provide a powerful and innovative new tool providing physicians more accurate atherosclerosis diagnosis, advancing the understanding of the pathophysiology of coronary artery disease, and facilitating the development of novel cardiovascular drugs and device therapies. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is one of the leading causes of mortality and morbidity - yet technologies to assess atherosclerotic plaque vulnerability are critically lacking. The goal of this project will be to enable new functional imaging approaches fo atherosclerosis using new ultra- broadband, multi-frequency circular arrays produced with micromachined piezoelectric composite (MPC) ultrasound transducer technology. This new intravascular ultrasound technology will enable enhanced imaging of adventitial neovasculature as well as molecular markers of inflammation, and has the potential to have a significant impact in the estimation of the risk of plaque rupture and assessment of atherosclerotic cardiovascular disease.